1H-furo[3,2-C]pyrazole compounds useful as kinase inhibitors

Abstract

Furo[3,2-c]pyrazole derivatives of formula (I) as defined in the description, and pharmaceutically acceptable salts thereof, wherein A is an aryl or heteroaryl ring, —NHZR5 is at the ortho position to the CONH linker; —R1 and R2 are the same or different and, independently from each other, represent a hydrogen atom, or an organic residue; R3 is a hydrogen or halogen atom or an organic group; R4 is a hydrogen or halogen atom or an organic group; Z is direct bond, >C═O, or —C(═O)NH—; —R5 is hydrogen or an optionally substituted organic group or isomers, tautomers, carriers, metabolites, prodrugs, and pharmaceutically acceptable salts thereof. A process for their preparation and pharmaceutical compositions comprising them are disclosed; the compounds of the invention may be useful, in therapy, in the treatment of diseases associated with a disregulated protein kinase activity, in particular Aurora kinases activity or IGF-1R activity, like cancer.

The invention claimed is: 
     
       1. A compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein
 A is an aryl or heteroaryl ring; 
 NHZR 5  is at the ortho position to the CONH linker; 
 R 1  and R 2  are the same or different and, independently from each other, represent a hydrogen atom, a straight or branched C 1 -C 3  alkyl, —CONH 2 , —CH 2 OR′ or —CH 2 NR′R″ or, taken together with the carbon atom to which they are bonded, R 1  and R 2  may form a C 3 -C 6  cycloalkyl group; R′ and R″ are the same or different and, independently from each other, represent a hydrogen atom or a straight or branched C 1 -C 3  alkyl group or, taken together with the nitrogen atom to which they are bonded, R′ and R″ may form a heterocyclic ring having one of the following formula 
 
       
       
         
           
           
               
               
           
         
         wherein R′″ is a hydrogen atom or a straight or branched C 1 -C 3  alkyl group;
 R 3  is a hydrogen or halogen atom or a group selected from hydroxy, cyano, straight or branched C 1 -C 3  alkyl, C 1 -C 6  alkylamino and C 1 -C 3  alkoxy; 
 R 4  is a hydrogen or halogen atom or a group selected from hydroxy, straight or branched C 1 -C 3  alkyl, C 1 -C 3  alkoxy, C 1 -C 6  alkylamino, C 1 -C 6  dialkylamino, azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, (1-methyl-piperazin-4-yl), (morpholino-4-yl), (azetidin-1-yl)methyl, (pyrrolidin-1-yl)methyl, (piperidin-1-yl)methyl, (1-methyl-piperazin-4-yl)methyl, (morpholino-4-yl)methyl, (1-methyl-piperidin-4-yloxy)methyl, (C 1 -C 6  alkylamino)methyl and (C 1 -C 6  di-alkylamino)methyl; 
 Z is a direct bond, —(C═O)—, or —C(═O)NH—; 
 R 5  is hydrogen or an optionally substituted group selected from C 1 -C 6  alkyl, C 1 -C 6  alkenyl, C 3 -C 6  cycloalkyl, aryl, heteroaryl and saturated heteroaryl; or optical isomers, tautomers and pharmaceutically acceptable salts thereof. 
 
       
     
     
       2. The compound of formula (I) as defined in  claim 1  wherein R1 and R2 are not hydrogen atoms. 
     
     
       3. The compound of formula (I) as defined in  claim 1  wherein A is an optionally further substituted thienyl, furyl, pyrrolyl or phenyl group. 
     
     
       4. The compound of formula (I) as defined in  claim 1  wherein A is a phenyl group and R4 is at 4 position relative to the CONH linker and represents hydrogen, halogen, methoxy, azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, (1-methyl-piperazin-4-yl), (morpholino-4-yl), (azetidin-1-yl)methyl, (pyrrolidin-1-yl)methyl, (piperidin-1-yl)methyl, (1-methyl-piperazin-4-yl)methyl, (morpholino-4-yl)methyl, (1-methyl-piperidin-4-yloxy)methyl, (C 1 -C 6  alkylamino)methyl or (C 1 -C 6  di-alkylamino)methyl group. 
     
     
       5. The compound of formula (I) as defined in  claim 1  wherein Z is —(CO)—. 
     
     
       6. The compound of formula (I) as defined in  claim 1  wherein R 1  and R 2  are both a methyl group or, taken together with the carbon atom to which they are attached, form a C 3 -C 6  cycloalkyl group. 
     
     
       7. The compound of formula (I) as defined in  claim 1  wherein R 3  represents a hydrogen or halogen atom. 
     
     
       8. A compound selected from the group consisting of:
 3-{2-[(1H-pyrrole-2-carbonyl)-amino]-benzoylamino}-1H-furo[3,2-c]pyrazole-5-carboxylic acid (1-methyl-1-phenyl-ethyl)-amide; 
 3-{2-[(thiophene-2-carbonyl)-amino]-benzoylamino}-1H-furo[3,2-c]pyrazole-5-carboxylic acid (1-methyl-1-phenyl-ethyl)-amide; 
 3-{2-[(1H-pyrrole-2-carbonyl)-amino]-benzoylamino}-1H-furo[3,2-c]pyrazole-5-carboxylic acid [1-(2-fluoro-phenyl)-1-methyl-ethyl]-amide; 
 3-{2-[(1-methyl-1H-pyrrole-2-carbonyl)-amino]-benzoylamino}-1H-furo[3,2-c]pyrazole-5-carboxylic acid (1-methyl-1-phenyl-ethyl)-amide; 
 3-{2-[(2-methyl-2H-pyrazole-3-carbonyl)-amino]-benzoylamino}-1H-furo[3,2-c]pyrazole-5-carboxylic acid (1-methyl-1-phenyl-ethyl)-amide; 
 3-{2-[(1-methyl-1H-pyrazole-3-carbonyl)-amino]-benzoylamino}-1H-furo[3,2-c]pyrazole-5-carboxylic acid (1-methyl-1-phenyl-ethyl)-amide; 
 3-(2-benzoylamino-benzoylamino)-1H-furo[3,2-c]pyrazole-5-carboxylic acid (1-methyl-1-phenyl-ethyl)-amide amide; 
 3-{2-[(5-methyl-1H-pyrazole-3-carbonyl)-amino]-benzoylamino}-1H-furo[3,2-c]pyrazole-5-carboxylic acid (1-methyl-1-phenyl-ethyl)-amide; 
 3-{2-[(thiazole-4-carbonyl)-amino]-benzoylamino}-1H-furo[3,2-c]pyrazole-5-carboxylic acid (1-methyl-1-phenyl-ethyl)-amide; 
 3-{4-(4-methyl-piperazin-1-yl)-2-[(1H-pyrrole-2-carbonyl)-amino]-benzoylamino}-1H-furo[3,2-c]pyrazole-5-carboxylic acid (1-methyl-1-phenyl-ethyl)-amide; 
 3-{4-(4-methyl-piperazin-1-yl)-2-[(1-methyl-1H-pyrrole-2-carbonyl)-amino]-benzoylamino}-1H-furo[3,2-c]pyrazole-5-carboxylic acid (1-methyl-1-phenyl-ethyl)-amide; and 
 3-{2-[(1-methyl-1H-imidazole-2-carbonyl)-amino]-benzoylamino}-1H-furo[3,2-c]pyrazole-5-carboxylic acid (1-methyl-1-phenyl-ethyl)-amide; 
 or optical isomers, tautomers, and pharmaceutically acceptable salts thereof. 
 
     
     
       9. A process for preparing the compounds of formula (I) and the pharmaceutically acceptable salts thereof as defined in  claim 1 , which process comprises:
 a) reacting a bi-cyclic compound of formula (II): 
 
       
         
           
           
               
               
           
         
         wherein ALK is a C 1 -C 4  alkyl group with any suitable pyrazole nitrogen atom protecting agent; 
         b) acylating the resultant compound of formula (III): 
       
       
         
           
           
               
               
           
         
         wherein ALK is as defined above and Q represents any suitable pyrazole nitrogen protecting group, with a compound of formula (IV): 
       
       
         
           
           
               
               
           
         
         wherein A and R 4  are as defined in  claim 1  and LG represents a suitable leaving group; 
         c) hydrolysing the alkyl ester group and removing of the protecting group Q from the resultant compound of formula (V): 
       
       
         
           
           
               
               
           
         
         wherein ALK, A, R 4  and Q are as defined above; 
         d) reacting the resultant compound of formula (VI): 
       
       
         
           
           
               
               
           
         
         wherein A and R 4  are as defined above, with a compound of formula (VII) 
       
       
         
           
           
               
               
           
         
         wherein R 1 , R 2  and R 3  are as defined in  claim 1 , in the presence of any suitable condensing agent; 
         e) reducing the nitro group of the resultant compound of formula (VIII) 
       
       
         
           
           
               
               
           
         
         wherein A, R 1 , R 2 , R 3 , R 4  and Q are as defined above; 
         either 
         f) acylating the resultant compound of formula (IX): 
       
       
         
           
           
               
               
           
         
         wherein A, R 1 , R 2 , R 3  and R 4  are as defined above, with a compound of formula (X) or (XI):
   R 5 —Z-LG  (X)
 
   R 5 —NCO  (XI)
 
 
         wherein Z is —(C═O)— or —C(═O)NH—, R 5  is as defined in  claim 1  and LG is as above defined; 
         g) selectively de-acylating the resultant compound of formula (XII): 
       
       
         
           
           
               
               
           
         
         wherein A, R 1 , R 2 , R 3 , R 4  and Q are as defined above and Z is —(C═O)— or —C(═O)NH—, by the selective hydrolysis of the ZR 5  substituent on the pyrazole nitrogen so as to obtain a compound of formula (I) wherein A, R 1 , R 2 , R 3  and R 4  are as defined above and Z is —(C═O)— or —C(═O)NH—, 
         or 
         f) treating a compound of formula (IX) as defined above with a carbonyl compound of formula W—CO—Y (XIII) wherein W and Y are hydrogen atoms or an optionally substituted group selected from C 1 -C 5  alkyl, C 1 -C 5  cycloalkyl, aryl, heteroaryl or saturated heteroaryl, in the presence of an opportune reducing agent, so as to obtain a compound of formula (I) wherein A, R 1 , R 2 , R 3  and R 4  are as defined above and Z is a direct bond and, if desired or necessary, 
         h) converting a compound of formula (I) as defined above into a different compound of formula (I) by known reactions, or converting a compound of formula (I) as defined above into a pharmaceutically acceptable salt or converting the salt thereof into the free compound of formula (I) as defined above. 
       
     
     
       10. A process for preparing a compound of formula (I) as defined in  claim 1 , which comprises:
 i) reducing the nitro group of the compound of formula (V): 
 
       
         
           
           
               
               
           
         
         and either 
         j) acylating the resultant compound of formula (XIV): 
       
       
         
           
           
               
               
           
         
         wherein A is an aryl or heteroaryl ring, R 4  is a hydrogen or halo en atom or a group elected from hydroxy, straight or branched C 1 -C 3  alkyl, C 1 -C 3  alkoxy, C 1 -C 6  alkylamino C 1 -C 6  dialkylamino, azetidin-1-yl, pyrrolidin-1-yl, piperidin-1yl, (1-methyl-piperazin-4-yl), (morpholino-4-yl), (azetidin-1-yl)methyl, (pyrrolidin-1-yl)methyl, (piperidin-1-yl)methyl, (1-methyl-piperazin-4-yl)methyl, (morpholino-4-yl)methyl, (1-methyl-piperidin-4-yloxy)methyl, (C 1 -C 6  alkylamino) methyl and C 1 -C 6 di-alkylamino) methyl, ALK is a C 1 -C 4  alkyl group with any suitable pyrazole nitrogen atom protecting agent and Q represents any suitable pyrazole nitrogen protecting group, with a compound of formula (IV): 
       
       
         
           
           
               
               
           
         
         with a compound of formula (X) or (XI):
   R 5 —Z-LG  (X)
 
   R 5 —NCO  (XI)
 
 
         wherein Z is —(C═O)— or —C(═O)NH—, R 5  is hydrogen or an optionally substituted group selected from C 1 -C 6  alkyl C 1 -C 6  alkenyl, C 3 -C 6  cycloalkyl, aryl, heteroaryl and saturated heteroaryl; or optical isomers, tautomers and pharmaceutically acceptable salts thereof and LG represents a suitable leaving group, so as to obtain a compound of formula (XV): 
       
       
         
           
           
               
               
           
         
         wherein A, R 4 , R 5 , ALK Q and Z are as defined above; 
         or 
         j′) treating a compound of formula (XIV) as defined above with a carbonyl compound of formula W—CO—Y (XIII) wherein W and Y are hydrogen atoms or an optionally substituted group selected from C 1 -C 5  alkyl, C 1 -C 5  cycloalkyl, aryl, heteroaryl or saturated heteroaryl, so as to obtain a compound of formula (XV) wherein A, R 4 , R 5 , ALK and Q are as defined above and Z is a direct bond; 
         k) hydrolysing the alkyl ester group and removing the protective group Q of the resultant compound of formula (XV) wherein Z is —(C═O)— or —C(═O)NH— or a direct bond; 
         l) reacting the resultant compound of formula (XVI) 
       
       
         
           
           
               
               
           
         
         wherein A, R 4 , R 5  and Z are as defined above, with a compound of formula (VII) 
       
       
         
           
           
               
               
           
         
         wherein R 1 , R 2  and R 3  are as defined in  claim 1 ; 
         m) converting a compound of formula (I) as defined above into a different compound of formula (I) by known reactions, or converting a compound of formula (I) as defined above into a pharmaceutically acceptable salt or converting the salt thereof into the free compound of formula (I) as defined above. 
       
     
     
       11. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined in  claim 1 , and at least one pharmaceutically acceptable excipient, carrier and/or diluent. 
     
     
       12. The pharmaceutical composition according to  claim 11  further comprising one or more chemotherapeutic agents. 
     
     
       13. A product or kit comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined in  claim 1 , or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined in  claim 1 , and at least one pharmaceutically acceptable excipient, carrier and/or diluent and one or more chemotherapeutic agent, as a combined preparation for simultaneous, separate or sequential use in anticancer therapy. 
     
     
       14. A method of inhibiting a kinase in vitro, the kinase selected from the group consisting of Aurora kinase and IGF-1R, which comprises contacting the kinase with an effective amount of a compound of formula (I).